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EDITORIAL |
Emory Program in Cardiovascular Outcomes Research and Epidemiology (P.W.F.W.), Emory University School of Medicine, Atlanta Veterans Affairs Medical Center Epidemiology and Genetics Section, Rollins School of Public Health at Emory University, and Endocrinology Section (G.E.U.), Emory University School of Medicine, Atlanta, Georgia 30306
Address all correspondence and requests for reprints to: Prof. Peter W. Wilson, Emory University School of Medicine, Department of Medicine/Cardiology, 1256 Briarcliff Road NE, Atlanta, Georgia 30306. E-mail: pwwilso{at}emory.edu.
Temporal changes (or secular trends) in the onset of menarche and pubertal maturation have been observed over the past two centuries. European populations have shown marked reductions in the age at menarche over the last 150 yr; the mean age at menarche was approximately 16–17 yr in the mid-19th century (1). In Eastern European countries, these decreases in age at menarche have occurred at a surprisingly consistent rate of around 1–3 yr for every 100 calendar years or 1–3.6 months per decade (2). A slower rate of decline for the timing of menarche has been reported in the United States. The National Health Examination Survey reported a drop of about 2.5 months in the average age of menarche during the time period between 1963–1970 and 1988–1994 (3). More recently, the age of menarche in the National Health and Nutrition Examination Survey III (1988–1994) and National Health and Nutrition Examination Survey 1999–2002 reported a further decline from 12.5 yr in 1988–1994 to 12.3 yr in 1999–2002 (4). Thus, these two national surveys indicate a decline in age at menarche of about 1 month per decade (approximately 1 yr for every 100 yr) in the United States. Reported differences in age at menarche across ethnic and racial groups indicate that Black girls on average experience menarche about 6 months earlier than White girls (4, 5). The mean menarcheal age in Black girls, however, is similar to the decline observed in White girls (
6 months) during the same period of time.
Girls with early menarche tend to be more obese and to have higher rates of cardiovascular risk factors as adults. A recent commentary by Slyper (6) provided an excellent summary of many of the key issues related to pubertal timing in American girls. He noted that insulin resistance "may be more prevalent in US children than previously recognized." He raised concerns that such insulin resistance may be accompanied by dyslipidemia (elevated triglycerides and low high-density lipoprotein cholesterol) and accelerated atherogenesis. The Bogalusa, LA, study, a long-term community-based study of cardiovascular risk factors since childhood, reported that both White and Black adult women who reported an age of menarche before age 12 have, on average, greater weight (+10 kg), body mass index (+4 kg/m2), and skin fold thicknesses (+6 mm) than women who underwent menarche after age 13.5 yr. In addition, the women with earlier menarche had a higher prevalence of hypertension and increased cardiovascular risk profiles (5). In addition, Bogalusa investigators reported that early menarche is associated with increased prevalence of hypertension, dyslipidemia, and insulin resistance, and the estimated odds for developing metabolic syndrome in adulthood was 1.54 (95% confidence interval, 1.14–2.07), regardless of race (7). Thus, a history of early menarche appears to increase future risk of developing diabetes, hypertension, and cardiovascular disease. Data supporting this have also been reported by European investigators who reported a long-term follow-up investigation of Danish schoolchildren (7, 8, 9).
The article by Casazza and colleagues (10) in this issue of JCEM investigates the determinants of pubertal transition in African-American and European-American girls. In contrast to previous epidemiological surveys on pubertal changes and age of menarche that used population approaches and cross-sectional or longitudinal designs, this study is a prospective study and includes dual-energy x-ray absorptiometry to assess adiposity, insulin response to an iv glucose challenge to evaluate insulin resistance, and endocrine hormone levels. Overall, these methods provide more detailed assessments than what has been generally available.
Casazza and colleagues’ (10) baseline data are based on findings in prepubertal girls at a mean age of 8 yr. They reported greater fasting insulin concentrations and evidence for more insulin resistance during an iv glucose tolerance test in Blacks compared with Whites. The Black girls subsequently experienced adrenarche approximately 0.8 yr earlier and menarche 0.9 yr earlier than their White counterparts. Multivariable regression analyses showed no relation between baseline levels of total fat mass, estrogen levels, and insulin resistance with age of menarche or between total fat mass estradiol levels and insulin levels or androgenic hormone levels dihydroepiandrosterone sulfate with adrenarche. On the other hand, Black race was significantly associated with greater insulin resistance during pubertal years (especially age 9–14 yr) and estradiol levels (generally age 7–13 yr) as well as lower age of both adrenarche and menarche. Even when adjusted for fat mass, Black girls tended to experience adrenarche and puberty earlier than White girls, and it is likely that insulin resistance plays a role. Further research into the mechanisms underlying these maturation changes are in order, with special consideration of adipokines, inflammatory markers, and hypovitaminosis D because the latter has been linked to greater insulin resistance, especially in Blacks (11, 12).
Greater body mass index in later childhood has been identified as a potential initiator of early menarche, but consensus is lacking on this topic and mechanisms have not been well characterized (13). Several studies have reported that children who are overweight or obese are more likely to become obese adults, and editorials have sounded the alarms over the dangers of childhood obesity, including higher blood pressure levels and greater risk of type 2 diabetes in adolescence and early adulthood (14, 15). In addition, investigators have reported that weight gain was especially likely to occur during adolescence when puberty occurred early as a consequence, and not a determinant of the age at menarche (6, 16).
The article by Casazza and colleagues (10) provides impressive evidence that Black girls are more insulin resistant, especially after age 9 yr. Insulin resistance may account for the occurrence of earlier menarche in this racial group, although the multivariable analyses they presented did not fully support the hypothesis. The baseline evaluation in their study was undertaken when the mean age of the girls was only 8 yr, and different results might be found with further study in older girls before menarche.
Future work into the mechanisms underlying early menarche will delve into the effects of insulin resistance in girls during their late childhood. Insulin resistance and the associated compensatory hyperinsulinemia can reduce levels of SHBG (17). SHBG is thought to regulate the bioavailability of sex steroids, and high insulin levels will potentially increase the bioavailability of sex steroids (18). In obese children, the greater bioavailability of sex steroids combined with putative increased adipocyte aromatase activity can increase the peripheral conversion of androgens to estrogens. Consequently, higher free sex hormone levels may feed back to the hypothalamus to activate gonadotropin secretion (19). Potentially, the elevated adrenal androgen levels and increased free sex steroid levels associated with the lower SHBG levels could promote activity of the GnRH pulse generator. In addition, obese children typically have higher levels of leptin (20), a proven permissive factor in initiating LH pulsatility and onset of puberty. This permissive effect has been confirmed by observations that recombinant leptin administration in older but not younger children with leptin deficiency results in increased gonadotropin pulsatility, (20) and more recently, leptin administration to women with secondary hypothalamic amenorrhea has been shown to increase LH pulsatility as well as ovarian volume, again suggesting a permissive role for leptin in the development of puberty (21). Although causality is not proven by these association studies, the link between insulin resistance and subsequent hormonal changes may explain the decline of age at menarche in obese children.
American girls are now experiencing puberty at a younger age than ever before, and there are challenges to elucidate the mechanisms that underlie these maturation changes. The critical need is for more longitudinal studies with periodic assessment of insulin resistance, adiposity, and hormonal effects to improve our understanding in this field.
Footnotes
Received April 22, 2008.
Accepted April 23, 2008.
References
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